The dopamine transporter (DAT) ligands are useful in evaluating changes in presynaptic DAT sites in vivo, especially for patients with Parkinson's disease (PD), which is characterized by a selective loss of dopamine neurons in the basal ganglia and substantia nigra. Based on the progress made in the past funding period, we propose to develop improved Tc-99m labeled dopamine transporter (DAT) imaging agents, specifically for in vivo imaging of CNS (central nervous system) with SPECT (single photon emission computed tomography). These new imaging agents will be useful as diagnostic tools for evaluation of CNS dopamine transporters in normal subjects and patients with Parkinson's disease. In the past few years, our laboratory has been engaged in developing Tc-99m labeled receptor specific imaging agents using [TcVO]+3N2S2 core. Technetium-99m (T1/2 = 6 hr) has several favorable characteristics: the radionuclide can be readily produced by a Mo-99/Tc-99m generator, the medium gamma-ray energy emitted by Tc-99m (140 KeV) is suitable for gamma camera detection and the physical half-life is compatible with the biological localization and residence time required for imaging. Advances in the technetium chemistry have significantly enhanced the development of Tc-99m radiopharmaceuticals for clinical use, and they will benefit millions of patients who receive Tc-99m agents in routine nuclear medicine diagnostic procedures. Efforts in searching for new Tc-99m imaging agents will have a significant impact on the future expansion of new diagnostic procedures and on the improvement of health care as a whole. The success in developing [99mTc]TRODAT-1 for CNS dopamine transporters (DAT) serves as the first example of Tc-99m site-specific imaging of human brain. The present project is a natural extension of this research effort. We propose to develop the second generation of Tc-99m based DAT imaging agents with several improved properties: higher brain uptake, selective binding to the DAT and formation of only one isomer. Synthesis and biological evaluations of the new Tc-99m labeled agents (in vitro binding study, in vivo biodistribution study in rats and SPECT imaging in baboons) are proposed. Testing of these additional novel tropane derivatives proposed in this project is necessary and worthwhile. If the novel DAT imaging agents are successfully developed, the new Tc-99m labeled imaging agents will be scientifically meaningful and clinically important for the diagnosis of Parkinson's disease.